Non-Invasive Method to Treat Urological and Gastrointestinal Disorders

ABSTRACT

Provided herein are methods and devices useful for inhibiting or treating urological conditions, such as overactive bladder (OAB) symptoms including bladder overactivity, urinary frequency, urinary urgency, urinary incontinence, interstitial cystitis (IC), urinary retention, and pelvic pain; gastrointestinal conditions, such as fecal incontinence, irritable bowel syndrome (IBS), and constipation; and sexual conditions, such as premature ejaculation, erectile disorder, and female sexual arousal disorder by non-invasive transcutaneous electrical stimulation of the foot.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/497,343, filed Sep. 10, 2012, which is a National Stage ofInternational Patent Application Number PCT/US2010/050883, filed Sep.30, 2012, which claims the benefit under 35 U.S.C. § 119(e) to U.S.Provisional Patent Application No. 61/247,659, filed Oct. 1, 2009, eachof which is incorporated herein by reference in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support under Grant Nos.DK-068566 and DK-077783 awarded by the National Institutes of Health.The government has certain rights in the invention.

BACKGROUND

It is well-known that electrical stimulation of somatic afferentpathways in the pudendal nerve, posterior tibial nerve, or sacral spinalroots can inhibit bladder activity in both humans and animals, and isclinically effective in treating overactive bladder symptoms.Stimulation of the sacral S3 spinal root is currently a FDA approvedtherapy for the lower urinary tract disorders including bladderoveractivity, urgency, frequency, incontinence, and urinary retention.Although the mechanisms underlying neuromodulation are uncertain, thistype of therapy has become popular because lower urinary tractdysfunctions in some patients are difficult to manage with medication.

However, sacral and pudendal neuromodulation requires surgery to implanta stimulator (e.g., InterStim®, Medtronic Inc.) and electrodes.Meanwhile, the standard treatment using tibial nerve neuromodulationinvolves 30 min stimulation once per week for 12 consecutive weeksthrough a percutaneously inserted needle electrode cephalad to themedial malleolus (Urgent PC® stimulator, Uroplasty Inc.). It requiresskilled medical staff to insert the needle electrode close to the nerveduring each clinical visit. If the initial 12 week treatment iseffective, a maintenance treatment (once every 2-3 weeks) is usuallyrequired. Thus, current neuromodulation treatments are effective tosuppress bladder overactivity, but they require surgery or repeatedclinical visits that are expensive and inconvenient. A non-invasiveneuromodulation method to treat overactive bladder could significantlyincrease the acceptance of neuromodulation treatment by more patientsand reduce the high medical cost of the treatment.

Several non-invasive neuromodulation approaches have been investigatedpreviously in an attempt to treat bladder overactivity, includingintra-vaginal (Lindstrom S, Fall M, Carlsson C A, Erlandson B E. Theneurophysiological basis of bladder inhibition in response tointravaginal electrical stimulation. J Urol 1983; 129: 405-410) orintra-anal (Godec C, Cass A S, Ayala G F. Bladder inhibition withfunctional electrical stimulation. Urol 1975; 6:663-666) simulationusing ring electrodes located on a vaginal/anal plug, dorsalpenile/clitoral nerve stimulation using transcutaneous electricalstimulation applied to the penis, or the perigenital/perianal skin area(Tai C, Shen B, Wang J, Chancellor M B, Roppolo J R, de Groat W C:Inhibitory and excitatory perigenital-to-bladder spinal reflexes in thecat. Am J Physiol Renal Physiol 2008; 294:F591-F602; Wheeler J S, WalterJ S, Zaszczurynski P J. Bladder inhibition by penile nerve stimulationin spinal cord injury patients. J Urol 1992; 147:100-103; Walter J S,Wheeler J S, Robinson C J, Wurster R D. Inhibiting the hyperreflexicbladder with electrical stimulation in a spinal animal model. NeurourolUrodyn 1993; 12:241-253; and Wang J, Liu H, Shen B, Roppolo J R, deGroat W C, Tai C: Bladder inhibition or excitation by electricalperianal stimulation in a cat model of chronic spinal cord injury. BJUInt 2009; 103:530-536). However, these approaches targeted veryinconvenient locations causing discomfort and difficulty in maintainingthe electrodes in place for an extended time period.

SUMMARY

The methods and devices described herein are useful for stimulating aphysiological response and for inhibiting or treating conditions, suchas overactive bladder (OAB) symptoms including bladder overactivity,urinary frequency, urinary urgency, urinary incontinence, interstitialcystitis (IC), urinary retention, and pelvic pain; gastrointestinalconditions, such as fecal incontinence, irritable bowel syndrome (IBS),and constipation; and sexual conditions, such as premature ejaculation,erectile disorder and female sexual arousal disorder.

The methods and devices are superior to prior methods because they donot involve invasive activities, such as electrode implantation, forinstance, as is currently used for urinary incontinence, and do notrequire precise placement of the electrodes. The methods involveelectrical stimulation applied to the skin of the foot of a patient,unexpectedly being able to inhibit bladder contractions in anon-invasive manner that is easily implemented by patients and which isamenable to use of garment electrodes, such as sock electrodes, greatlyenhancing patient independence and reducing costs of such procedures.

A method of stimulating a physiological response in a subject isprovided. The method comprises applying transcutaneous electrical pulsesranging from 1 Hz to 500 Hz and from 1V to 50V to the patient's foot(one or both feet of the patient) effective to stimulate a physiologicalresponse selected from the group consisting of inhibiting or treating inthe patient one or more of: bladder contractions; rectum contractions;bulbospongiosus and ischiocavernosus muscle contractions; urologicalconditions, such as overactive bladder (OAB) symptoms including bladderoveractivity, urinary frequency, urinary urgency, urinary incontinence,interstitial cystitis (IC), urinary retention, and pelvic pain;gastrointestinal conditions, such as fecal incontinence, irritable bowelsyndrome (IBS), and constipation; and sexual conditions, such aspremature ejaculation, erectile disorder, and female sexual arousaldisorder. In one embodiment, the method comprises inhibiting bladdercontractions in a patient by applying transcutaneous electrical pulsesranging from 1 Hz to 500 Hz, 0.1 ms to 3 ms and from 1V to 50V to thepatient's foot effective to inhibit bladder contractions in the patient.The electrical pulses are applied in certain embodiments by one or moreelectrodes on skin of the dorsal side of the patient's foot about one ormore metatarsal bones and one or more opposite electrodes (an “oppositeelectrode” is one that is oppositely charged in relation to another,e.g. a cathode is an opposite electrode to an anode) on skin of theplantar side of the patient's foot about one or more metatarsal bones.In another embodiment, the electrical pulses are applied by one or moreelectrodes on skin of the dorsal side of the patient's foot about one ormore metatarsal bones and one or more opposite electrodes on skin of thedorsal side of the patient's foot about one or both of the talus,cuboid, intermediate cuneiform, lateral cuneiform or navicular bones. Inyet another embodiment, the electrical pulses are applied by one or moreelectrodes on skin of the plantar side of the patient's foot about thetarsal bones and one or more opposite electrodes on skin of the plantarside of the patient's foot about the calcaneous bones. The electrode maybe any useful electrode configuration for stimulation the foot, forexample a garment electrode, such as a sock electrode.

The electrical pulses may be any waveform, or mixture thereof, effectiveto stimulate the desired response. In one embodiment, the pulses arebiphasic, symmetrical and/or rectangular and preferably the biphasicpulses are charge-balanced. The pulses can be applied for any effectivetime period or pattern. For example, in one embodiment, the pulses areapplied in two or more stimulation intervals of from 0.5 to 200 secondswith a rest period of no electrical stimulation able to cause bladder orrectal inhibition during stimulation intervals. In another embodiment,the pulses are applied at a voltage less than an intensity threshold toinduce toe movement (T) in a patient. In certain embodiments, the pulsefrequency ranges from 1 to 50 Hz, 5 to 20 Hz or is approximately 5 Hz.In certain embodiments, the voltage ranges from 3V to 12V and may rangefrom 0.5T to 2T, where T is the toe-twitch threshold of a patient. Incertain embodiments, the pulse duration ranges from 0.1 to 3 ms, 0.2 to1 ms or is approximately 1 ms.

Also provided is a device for use in stimulating a physiologicalresponse in a patient for inhibiting or treating in the patient one ormore of: bladder contractions; rectum contractions; bulbospongiosus andischiocavernosus muscle contractions; urological conditions, such asoveractive bladder (OAB) symptoms including bladder overactivity,urinary frequency, urinary urgency, urinary incontinence, interstitialcystitis (IC), urinary retention, and pelvic pain; gastrointestinalconditions, such as fecal incontinence, irritable bowel syndrome (IBS),and constipation; and sexual conditions, such as premature ejaculation,erectile disorder, and female sexual arousal disorder. The devicecomprises an electrical pulse generator, an electrode assemblycomprising two or more skin surface electrodes configured to positionelectrodes on a patient's foot such that the electrodes can be used tostimulate the physical response and leads (e.g., wire leads) connectingthe electrodes to the pulse generator, wherein the pulse generator isconfigured to produce electrical pulses in the range of from 1 Hz to 500Hz and from 1V to 50V to stimulate the physiological response in thepatient. In one embodiment, the electrodes are in a garment electrodefor the foot, such as a sock electrode. In certain embodiments, thepulse frequency ranges from 1 to 50 Hz, 5 to 20 Hz or is approximately 5Hz. In certain embodiments, the voltage ranges from 3V to 12V and mayrange from 0.5T to 2T, where T is the toe-twitch threshold of a patient.In certain embodiments, the pulse duration ranges from 0.1 to 3 ms, 0.2to 1 ms or is approximately 1 ms.

According to certain embodiments, the pulse generator is attached to agarment electrode for a foot comprising the electrodes and comprises anantenna and the pulse generator is controllable by an externaltransmitter that transmits a signal that is received by the antenna ofthe pulse generator and data can be transmitted from the pulse generatorto an external receiver. In one embodiment, the external receiver iscontained in a device comprising the transmitter. In certainembodiments, the external transmitter transmits an identification signalto the pulse generator, the pulse generator requiring an appropriateidentification signal from the transmitter to control output of thepulse generator. In another embodiment, one of the pulse generator andthe transmitter comprises an RFID tag and the other of the pulsegenerator and the transmitter comprises an RFID reader and verificationof the identity of the pulse generator and transmitter by RFID isrequired to control output of the pulse generator. In yet anotherembodiment, signals from the transmitter are encrypted and can only bedecrypted by a matching pulse generator. As a safety measure, in oneembodiment of the device, one of the pulse generator and the transmitterrequire identification of the other before the transmitter can controloutput of the pulse generator

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram of one non-limiting embodiment of a deviceuseful in implementing methods described herein.

FIGS. 2A and 2B show schematically two embodiments of garment electrodeassemblies useful in a device such as the device depicted in FIG. 1

FIG. 3: Electrode placement for electrical stimulation of the cat hindfoot.

FIG. 4: Inhibition of isovolumetric bladder contractions by electricalstimulation applied to the hind foot via 3 different electrodeconfigurations (A-C) as shown in FIG. 3. Stimulation of the front footwas not effective in inhibiting the bladder (D). The thin lines underthe pressure traces indicate zero pressure. Black bars under thepressure traces indicate the stimulation duration. Stimulation pulsewidth was 1 ms. T=threshold to induce toe twitching. Data were from 4different cats.

FIG. 5: Inhibition of isovolumetric bladder contractions by 5 Hzelectrical stimulation of the foot. A. Complete inhibition was achievedat one half of the intensity threshold (T=6 V) for inducing toe movementwith electrodes 1-2. B. Complete inhibition was achieved at 2 times ofthe intensity threshold (T=4 V) for inducing toe movement withelectrodes 1-3. The thin lines under the pressure traces indicate zeropressure. Black bars under the pressure traces indicate the stimulationduration. Stimulation pulse width was 1 ms. Data in A and B were fromthe same animal.

FIG. 6: Bladder capacity was increased by electrical stimulation of thefoot at different frequencies (5 or 20 Hz). Stimulation intensity (12 V)was at 2 times of intensity threshold to induce toe movement.Stimulation pulse width was 1 ms. Electrodes 1-2 were used. The arrowsindicate the start and stop of bladder infusion (2 ml/min). The blackbars under the pressure traces indicate the stimulation duration.

FIG. 7: Bladder capacity was significantly increased by electricalstimulation of the foot at different frequencies (5 or 20 Hz).Stimulation intensity (3-12 V) was at 1-2.5 times of intensity thresholdto induce toe movement. Stimulation pulse width was 1 ms. Data were fromtotal 5 cats. Electrodes 1-2 were used in 3 cats, and electrodes 1-3were used in another 2 cats. * indicates statistical significance(P<0.05).

FIG. 8: Foot stimulation inhibited bladder overactivity induced by 0.25%acetic acid (AA). A. 0.25% AA irritated bladder, caused bladderoveractivity, and reduced bladder capacity during CMG. The arrowsindicate the start and stop of the infusion (2 ml/min). B. Theoveractive bladder contractions under isovolumetric condition at asmaller bladder volume as shown in A was inhibited by foot stimulation.The thin lines under the pressure traces indicate zero pressure. Blackbars under the pressure traces indicate the stimulation duration.Stimulation pulse width was 0.2 ms. Electrodes 1-2 were used.

FIG. 9: Reduction in bladder capacity induced by 0.25% acetic acid (AA)was partially reversed by foot stimulation at different frequencies (5or 20 Hz). Stimulation intensity (10 V) was at 1.25 times of intensitythreshold to induce toe movement. Stimulation pulse width was 1 ms.Electrodes 1-2 were used. The arrows indicate the start and stop ofbladder infusion (2 ml/min). The black bars under the pressure tracesindicate the stimulation duration.

FIG. 10: Reduction in bladder capacity induced by 0.25% acetic acid (AA)was partially reversed by foot stimulation at different frequencies (5or 20 Hz). Stimulation intensity (6-12 V) was at 1.25-3 times ofintensity threshold to induce toe movement. Stimulation pulse width was1 ms. Electrodes 1-2 were used in total 4 cats. * indicates statisticalsignificance (P<0.05).

DETAILED DESCRIPTION

The use of numerical values in the various ranges specified in thisapplication, unless expressly indicated otherwise, are stated asapproximations as though the minimum and maximum values within thestated ranges are both preceded by the word “about”. In this manner,slight variations above and below the stated ranges can be used toachieve substantially the same results as values within the ranges.Also, unless indicated otherwise, the disclosure of ranges is intendedas a continuous range including every value between the minimum andmaximum values. As used herein “a” and “an” refer to one or more.

The ranges provided herein for e.g., electric pulse frequencies arebased on experimentation on cats. Nevertheless, the frequenciesnecessary to elicit a desired response in humans is very similar. Asillustrated in U.S. Pat. No. 7,047,078, stimulation of the pudendalnerve in human subjects produce similar results as compared to theresults in cats. As such, frequency ranges applicable to cats areconsidered to be effective in humans.

Stimulus effective to inhibit bladder contractions is expected to alsoaffect gastrointestinal and sexual conditions including: urologicalconditions, such as overactive bladder (OAB) symptoms including bladderoveractivity, urinary frequency, urinary urgency, urinary incontinence,interstitial cystitis (IC), urinary retention, and pelvic pain;gastrointestinal conditions, such as fecal incontinence, irritable bowelsyndrome (IBS), and constipation; and sexual conditions, such aspremature ejaculation, erectile disorder and female sexual arousaldisorder. For example, sacral neuromodulation (e.g., InterStim,Medtronic Inc) can treat both overactive bladder and urinary retention.In another example, transcutaneous stimulation of the tibial nerveapproximately 10 cm above the ankle has shown some limited potential inalleviating urinary and fecal incontinence (see e.g., Queralto et al.Preliminary results of peripheral transcutaneous neuromodulation in thetreatment of idiopathic fecal incontinence Int J Colorectal Dis (2006)21: 670-672 and Vitton et al. Transcutaneous Posterior Tibial NerveStimulation for Fecal Incontinence in Inflammatory Bowel DiseasePatients: A Therapeutic Option? Inflamm Bowel Dis 2009; 15:402-405),though these methods are sub-optimal because they require preciseplacement of the electrode over the tibial nerve and are not believed tostimulate substantially, if at all, any nerves in addition to the tibialnerve. It is believed that sacral neuromodulation modulates the centralnervous system (CNS) by stimulating the sacral root and sending neuralactivity into the CNS. This neuromodulation input can make the CNSbalance to one way the other, that is, if it is overactive bladder itwill make the CNS to be more inhibitory to the bladder activity, but ifit is urinary retention, then the neuromodulation will make the CNS moreexcitatory to the bladder. The underlying mechanisms are very complexand not fully understand yet.

The foot stimulation methods described herein are another type ofneuromodulation. They send modulatory neural signal from the foot nervesto the CNS. The Examples below show that this foot neuromodulation canmodulate the CNS to inhibit the bladder. This does not mean that footneuromodulation can only induce inhibitory effect. When the pathologicalcondition is the opposite (for example, urinary retention), the footneuromodulation should be able to modulate the CNS to facilite bladdercontraction or facilite voiding. In summary, foot stimulation is anothertype of neuromodulation that can induce either inhibitory or excitatoryeffect depending on the state of the CNS (that is, exciting orinhibiting an organ). Now, we know that stimulation of the foot nerve(somatic nerve) can modulate the bladder (autonomic organ), therefore itis logical and reasonable to conclude it will also modulate otherautonomic organs (e.g., defecation or sexual functions).

It should also be recognized that the optimal stimulation parameters toelicit a desired effect may vary to some degree from subject-to-subject,depending on a number of factors. Optimal frequencies to elicit thedesired goals can be adjusted from person-to-person. A “patient” may behuman or animal and unless specified otherwise embraces a specificpatient, a class of patients or any human or animal in a generic sense.Thus, a structure configured to, or adapted to, a patient's footincludes structures configured to a specific patient and/or a group ofpatients.

According to one non-limiting embodiment, method of inhibiting orcontrolling one or more of bladder contractions; rectum contractions;bulbospongiosus and ischiocavernosus muscle contractions; urination;defecation; ejaculation; and pelvic pain of the bladder, urethra,prostate, anus or rectum in a patient is provided. The methods areuseful in inhibiting or treating urological conditions, such asoveractive bladder (OAB) symptoms including bladder overactivity,urinary frequency, urinary urgency, urinary incontinence, interstitialcystitis (IC), urinary retention, and pelvic pain; gastrointestinalconditions, such as fecal incontinence, irritable bowel syndrome (IBS),and constipation; and sexual conditions, such as premature ejaculation,erectile disorder and female sexual arousal disorder. In one embodimentthe method is directed to a method of inhibiting bladder contractions,bowel and/or rectum contractions, and therefore urination and/ordefecation in a patient. The method comprises inhibiting one or more ofbladder contractions, bowel and/or rectum contractions, and thereforeurination and/or defecation in the patient by applying an electricalsignal to the foot of a patient.

Either one or both (left and right) of the feet can be stimulatedconcurrently, alternately or in any useful sequence to achieve thedesired results. Most generally, electrodes are positioned on the footat a position such that when electric pulses of sufficient voltage,duration and frequency to inhibit bladder or GI contractions is applied,the stimulus can be used to treat urological conditions, such asoveractive bladder (OAB) symptoms including bladder overactivity,urinary frequency, urinary urgency, urinary incontinence, interstitialcystitis (IC), urinary retention, and pelvic pain; gastrointestinalconditions, such as fecal incontinence, irritable bowel syndrome (IBS),and constipation; and sexual conditions, such as premature ejaculation,erectile disorder, and female sexual arousal disorder. Certainparameters are discussed below which are expected to elicit such aresponse in a patient. Nevertheless, the following ranges andembodiments are exemplary and any variation from the stated rangescapable of eliciting the desired response is considered to be within thescope of the methods described herein. As such any methods or devicesdescribed herein are expected to be useful for controlling or treatingurological conditions, such as overactive bladder (OAB) symptomsincluding bladder overactivity, urinary frequency, urinary urgency,urinary incontinence, interstitial cystitis (IC), urinary retention, andpelvic pain; gastrointestinal conditions, such as fecal incontinence,irritable bowel syndrome (IBS), and constipation; and sexual conditions,such as premature ejaculation, erectile disorder and female sexualarousal disorder or any other disease or condition that would benefitfrom relief of contractions in the lower pelvis (e.g., contractions ofthe bladder or rectum).

Any positioning of an electrode pair on the foot (to include the anklejoint, that is, at or below the ankle (talocrural) joint of a patient)that is useful in inhibiting bladder, rectal or ejaculatorycontractions/activity are considered within the scope of the presentmethods and devices and alteration of the specific positioning describedbelow that are useful in the described methods are considered to bewithin the scope of the described methods. The following is adescription of three exemplary positioning for the electrodes: 1) twoelectrodes attached on the bottom of the foot, between one or moremetatarsal bones and calcaneus bones; 2) two electrodes attached on topof the foot: between one or both of the talus, cuboid, intermediatecuneiform, lateral cuneiform or navicular bones and one or moremetatarsal bones; or 3) two electrodes attached one on top and anotheron the bottom of the foot: across the metatarsal bones.

These configurations do not necessarily stimulate one particular nervebecause the electrical pulses pass through the foot and are not targetedto specific nerves. Although there are other nerves in the foot, withoutany attempt to be bound by this theory, the methods described hereinstimulate the peroneal and tibial nerves and/or branches thereof, suchas the medial plantar and lateral plantar branches of the tibial nerve.As used herein, the electrodes are said to be on skin “about” a specificbone (e.g. about one or more metatarsal bones) when they are placed,located (etc.) on skin that covers or partly covers the specifiedbone—that is, the specified bone lies partially or wholly underneath theskin said to be “about” the specified bone. Skin “about” a specifiedbone can overlap the specified bone and another bone.

The electrodes can be any skin surface electrode, such as, withoutlimitation, self-adhesive skin surface electrodes. For example, a largevariety of useful electrodes and electrode configurations are well-knownin the medical arts and are available commercially for use in, e.g.,TENS (Transcutaneous Electrical Nerve Stimulation), NMES (NeuromuscularElectrical Stimulation), patterned Electrical Neuromuscular Stimulation(PENS), and Interferential Current (IFC), methods and devices.Alternately, the electrodes can be built into a sock, shoe, bandage,wrap or other foot covering so that the described methods can beperformed discretely, e.g., at work. For instance electrode socks areavailable for diabetic foot care, though the electrodes are notnecessarily configured to be useful for the purposes described herein.Commercial examples of sock devices (electrode sock) include theELECRO-MESH™ garments (Prizm Medical, Inc. of Oakwood Ga.). UnitedStates Patent Publication No. 20040254624 describes various garmentelectrode devices. So long as the electrode is capable of delivering anelectrical current to the skin of a patient when placed on a patient'sfoot at a position useful in the methods described herein, it isconsidered to be useful in the methods and devices described herein.

Structures comprising electrodes, such as shoes (sneakers, sandalsetc.), socks, wraps, bandages (including ankle/foot supports or braceproducts comprising, e.g., neoprene), etc. that are useful in themethods and devices described herein and can be formed in anyconfiguration or structure that facilitates positioning and contact ofthe electrodes with the foot. A “garment electrode” is an electrodeassembly configured to replicate a piece of clothing, such as a sock,shoe, wrap, support or bandage, comprising electrodes configured tocontact a patient's skin, e.g., in a position useful for inhibitingbladder contractions in the methods described herein. In one embodiment,a garment electrode is a wrap with Velcro (hook and loop) closures thatfits around a patient's foot. FIGS. 2A and 2B, described below, depictsschematically non-limiting examples of such structures.

Description of all possible effective structures is impossible. As such,an electrode assembly “configured to” position electrodes on a patient'sfoot for inhibiting bladder contractions, GI contractions and/orejaculation, or “configured for” use in inhibiting bladder contractions,GI contractions and/or ejaculation in a patient, is intended to embracethose electrode assemblies that are useful any method or devicedescribed herein. As indicated above, the structure may be designed tofit a specific patient, group of patients (e.g. a women's size 8 (US)shoe, or a men's size 10-13 (US) shoe) or all or substantially allpatients (e.g., one size fits all).

The electrical signal comprises administering electrical pulseseffective to inhibit bladder and/or bowel contractions or ejaculation.This is thought to produce a storage stage, similar to the typicalstorage stage of the normal micturition or defecation processes. Theinhibitory or blocking electrical signal is thought to inhibitcontraction of one or both of the external urethral sphincter and theanal sphincter of the subject. As will be recognized by a person ofskill in the art, characteristics of electrical pulse, including,without limitation, amplitude (pulse strength, referring to themagnitude or size of a signal voltage or current), voltage, amperage,duration, frequency, polarity, phase, relative timing and symmetry ofpositive and negative pulses in biphasic stimulation, and/or wave shape(e.g., square, sine, triangle, sawtooth, or variations or combinationsthereof) may be varied in order to optimize results in any particularsubject or class of subjects. Subjects may be classified by species,disease/condition, sex, or any other factor that can be generalized to agroup. Stated ranges are intended to include all values and rangeswithin the stated ranges. So long as other characteristics of theelectrical signals (e.g., without limitation, amplitude, voltage,amperage, duration, polarity, phase, relative timing and symmetry ofpositive and negative pulses in biphasic stimulation, and/or wave shape)are within useful ranges, modulation of the pulse frequency will achievea desired result. Useful values for those other characteristics arewell-known in art and/or can be readily established by routineexperimentation, for instance by the ability to prevent voiding bymethods described herein.

One characteristic of the electrical signals used to produce a desiredresponse, as described above, is pulse frequency. Although effectiveranges (e.g., frequencies able to produce a stated effect) may vary fromsubject-to-subject, and the controlling factor is achieving a desiredoutcome, certain, non-limiting exemplary ranges may be as follows. Forinhibiting bladder, bowel or sexual gland/muscle contractions, thosefrequencies may range from approximately 1 Hz (Hertz, or pulses persecond) to approximately 500 Hz, though in practice, the range may bemore typically 1-50 Hz, the range typically used for human nervestimulation. Data below shows a range of at least from 5-20 Hz, with 5Hz pulses being preferred in some instances. Useful pulse durationstypically range from 0.1 to 3.0 ms (milliseconds), for example 0.2-1.0ms or 1 ms pulses.

Another characteristic of the pulses are the Voltage. Nerve stimulationcan be achieved in a typical range of from 1-50V, for example 3-15V asshown in the Examples below, with a range of from 1 to 15-20V beingpreferred in many instances. The typical voltage for foot stimulationmay be from 0.25 to 5 times the toe twitch motility threshold (0.25T-5T,where the pulses case toe twitching). In some instances bladder, bowel,ejaculation and/or pelvic pain inhibition may be achieved at voltagesless than 1.0T, such that the electrical stimulation causes no foottwitch, but has the desired inhibitory effect (see, e.g., FIG. 5A, where0.5T pulses are shown to be able to inhibit bladder contractions).

As indicated above, the waveform of the pulses may vary, so long as thedesired inhibitory effect is realized. One skilled in the art willappreciate that other types of electrical stimulation may also used inaccordance with the present invention. Monophasic or biphasic stimuli,or a mixture thereof may be used. Biphasic stimulus may be preferred asthere is less chance of tissue damage over the long-term. Damage tonerves by the application of an electrical current may be minimized, asis known in the art, by application of biphasic pulses or biphasicwaveforms to the nerve(s), as opposed to a monophasic pulses orwaveforms that can damage nerves in some instances of long-term use.“Biphasic current,” “biphasic pulses” or “biphasic waveforms” refer totwo or more pulses that are of opposite polarity that typically are ofequal or substantially equal net charge (hence, biphasic and chargebalanced) and may be symmetrical asymmetrical or substantiallysymmetrical. This is accomplished, for example, by applying through anelectrode one or more positive pulses, followed by one or more negativepulses, typically of the same amplitude and duration as the positivepulses, or vice versa, such that the net charge applied to the target ofthe electrode is zero or approximately zero. The opposite polaritypulses may have different amplitudes, profiles or durations, so long asthe net applied charge by the biphasic pulse pair (the combination ofthe positive and negative pulses) is approximately zero.

The waveform may be of any useful shape, including without limitation:sine, square, rectangular, triangle sawtooth, rectilinear, pulse,exponential, truncated exponential, damped sinusoidal. The pulses mayincrease or decrease over the stimulus period. The pulses may be appliedcontinuously or intermittently as needed. As indicated below,stimulation of the foot at certain voltages for certain time periodselicits post-stimulus inhibition of bladder contractions. Therefore, thestimulus may be applied for short intervals (e.g. 1-10 minutes) toachieve longer-lasting relief, in terms of hour or days. The stimulusmay be applied intermittently (that is, the pulses are turned on and offalternately during a stimulus interval for any time period) duringcontinuous or interval stimulus protocols. For example, the stimulus maybe applied for 5 seconds on and 5 seconds off over an interval of, forexample, 1-10 minutes or longer. Other non-limiting examples ofintermittent application of pulses may be 1-90 seconds on and 1-90seconds off over a 1-30 minute time period. So long as other pulseparameters are within acceptable limits, the inhibition is temporary anddoes not damage the involved nerves.

In another embodiment, a device or system for use in inhibiting in apatient one or more of: bladder contractions; rectum contractions;bulbospongiosus and ischiocavernosus muscle contractions; urination;defecation; ejaculation; and pelvic pain of the bladder, urethra,prostate, anus or rectum is provided. The system comprises a pulsegenerator unit configured to produce electric pulses able to inhibitcontraction of the bladder or bowel or to inhibit ejaculation. Asindicated above, the frequency ranges from 1 Hz to 500 Hz, such as 1-50Hz, 5-20 Hz, or 5 Hz. Voltage may range from 1-50V, such as from 1-20Vor from 3-15V. The device or system may be set to produce pulsescontinuously or intermittently as described above, and can becontrollable by the patient. The device also comprises an electrodeassembly configured to or adapted for placement of two or moreelectrodes on the foot of a patient in a position suitable for producingthe desired stimulation in the methods described herein.

In practice, the pulse generator may be programmable, programmed,non-programmable, or otherwise adapted to or configured to producepulses within the ranges described herein as being useful for the statedpurpose. For example, a commercial multi-purpose electrical stimulatorfor use in, e.g., TENS or NEMS, may be adjusted to the parameters usefulin the methods described herein. In one non-limiting example, the deviceis non-programmable, having a pre-fixed output for voltage, pulsefrequency, pulse length, and/or stimulus pattern/interval that cannot bechanged. For instance, in one embodiment, the device produces 1 mspulses at 5 Hz and 11V for 150 seconds whenever the device is activatedeither by the patient or another, or at specific intervals, for examplehourly. Other settings may be any useful stimulation parameters withinthe ranges described above as being useful in the methods describedherein. In another example, the device has two or more pre-fixedsettings that cannot be changed, so that a patient or health careprovider can choose the most effective stimulation parameter for thepatient or for the patient's particular circumstances (e.g., in ameeting versus before bed). The frequency might be adjustable orachieved in any manner within any range described herein. Programmableor fixed-output electrical pulse generators are common and configurationto the stimulation parameters described herein is well within theabilities of those of ordinary skill in the art.

The pulse generation unit may comprise a first wireless communicationsystem for receiving control instructions from a wireless controller;and a wireless controller, comprising an input, an optional display anda second wireless communication system configured to send controlinstructions to the pulse generator. In one embodiment, the electricpulses are biphasic. The first wireless communication system may alsotransmit status information for the pulse generator to the wirelesscontroller. Further description of one embodiment of such a system isdescribed in reference to FIG. 1. The phrases “configured to” and“adapted to” and like terms or phrases refer to the manufacture,production, modification, etc. of a device or system to produce adesired function. In the context of the devices or systems describedherein, a device or system “adapted to” or “configured to” produce adesired output is a device programmed of otherwise manufactured,produced, modified, etc. in any manner to produce the stated effect.

FIG. 1 depicts schematically one non-limiting embodiment of atwo-channel system for stimulating foot nerves according to the methodsdescribed herein. Pulse generator 10 is depicted as having two outputchannels. Wire leads 12 and 13 are attached to electrodes 14 and 15,which are placed across the metatarsal region of a foot 20. Electrode 15is shown on the plantar side of the foot while electrode 14 is shown onthe plantar side of the foot. Output parameters of the pulse generator10 can be controlled via a wired interface, but also may be controlledby wireless transmission, which can be carried any suitable wirelessprotocol, such as radio frequency, IEEE 802.11a/b/g/n, Bluetooth, etc.Thus, an external controller 30 is depicted for communicating with thepulse generator 10. External controller 30 is depicted as having adisplay 32, such as an LCD, LED or OLED display, and a keypad 34 forentering data into the external controller 30. External controller isdepicted as sending a wireless transmission 36 to pulse generator 10,though in another embodiment, data can be transferred both to the pulsegenerator 10 from the external communicator 30 and vice-versa, to permitmonitoring of one or more parameters of pulse generator 10, including,without limitation, output signal characteristics (e.g., frequency,amplitude, etc. as outlined above) and battery strength. Likewisewireless transmission 36 can be replaced by a wire or other conductor.Activity of pulse generator 10 and external controller 30 typically ismicroprocessor controlled and software/firmware installed onto the pulsegenerator 10 and external controller 30 hardware may be used toimplement the described tasks, and to provide, for example and withoutlimitation, a GUI (graphical user interface) for the display 32, whichfacilitates use of the system. Both pulse generator 10 and externalcontroller 30 may comprise any suitable electrical and electroniccomponents to implement the pulse, communication, feedback, adjustment,etc. activities, including, microprocessors, memory (e.g., RAM, ROM.Flash memory, etc.), connectors, batteries, power transformers,amplifiers, software (including, for example and without limitation:firmware, operating systems, utilities, processes, routines), etc. Aperson of skill in the electronic arts will be able to implement such asystem using readily-available electronics parts and ordinaryprogramming skills. Proprietary chips, chipsets, etc. may be designedand manufactures to implement the devices described herein.

External controller 30 may be a proprietary device that is specificallydesigned for the task, or a non-proprietary device, such as a commercialTENS controller, smart phone or a portable computer. Pulse generator 10may comprise any number of channels, so long as the number of channelsneeded to implement a desired method is provided. In one variation ofthe embodiment depicted in FIG. 1, one or both of wire leads 12 and 13are split into two or more wire leads, each of which are terminated in aseparate electrode, so that more than one region of the foot isstimulated.

One potential difficulty with use of wireless devices is one ofidentity. A controller should only be able to control one pulsegenerator to prevent accidental stimulation of unintended subjects, oreven intentional stimulation. In its simplest form, the transmissionrange of the devices can also be limited to prevent transmission overdistances more than a few feet, thereby limiting the chances ofunintended stimulation (crosstalk). Also, any number of identityverification mechanisms may be utilized to prevent crosstalk. In oneembodiment, different transmission wavelengths may be used for differentdevices, thus lowering the likelihood of crosstalk. In anotherembodiment, the pulse generator is programmed to only respond to atransmission containing a pre-defined signal, such that the pulsegenerator and external wireless controller must first, and/orperiodically “handshake” in order to communicate. Likewise, the pulsegenerator and/or controller may transmit encrypted signals which onlycan be decrypted by a key stored in the other of the pulse generatorand/or controller. In another embodiment, RFID tagging technology may beused to ensure that the controller and pulse generator match. Anycombination of these proximity and/or identity verification measures maybe used to prevent cross-talk. Other useful technologies for ensuringsecurity and identity in communication are, or may be available and areequally applicable.

FIG. 2A depicts schematically one embodiment of a garment electrodeassembly 100. An inward-facing (toward the foot) surface of theelectrode assembly 100 is shown. Electrode assembly may be a fabric orcomposite material, such as neoprene or latex and fabric material. Theelectrode assembly 100 has four wings 110 that wrap around a patient'sfoot. On each wing 110 is depicted a portion of a hook and loop fastener(e.g., Velcro®). Wings 110 on the left side of FIG. 2A have a hookportion 120 of a hook and loop fastener shown on the inward-facingsurface of the assembly. Wings 110 on the right side of FIG. 2A have aloop portion 121 of a hook and loop fastener shown in phantom on theopposite, outward-facing surface of the assembly. Of course theplacement of the hook and loop portions are a matter of design choiceand one or both hook and loop pairs depicted may be reversed. Electrodes131 and 132 for contacting a patient's foot are depicted on theinward-facing surface of the electrode assembly 100. Electric leads 134and 135 are shown for connecting the electrodes 131 and 132 to a pulsegenerator. This embodiment would be useful where the electrodes are bothplaced on the plantar or dorsal side of the foot.

FIG. 2B depicts schematically a garment electrode assembly 200 thatwould be useful for stimulating across the foot, e.g., with oneelectrode on the dorsal side of the metatarsals of a patient and theother on the plantar side. A hook portion 220 of a hook and loopfastener is shown on the inward-facing surface of the assembly 200 onthe left side of FIG. 2B. A hook portion 221 of a hook and loop fasteneris shown in phantom on the outward-facing surface of the assembly 200 onthe right side of FIG. 2B. Electrodes 231 and 232 for contacting apatient's foot are depicted on the inward-facing surface of theelectrode assembly 100. Electric leads 234 and 235 are shown forconnecting the electrodes 231 and 232 to a pulse generator.

Also provided herein is a method of stimulating a physiological responsein a subject. The method comprises stimulating nerves of the foot of apatient using surface (skin) electrodes with electrical pulses at afrequency and amplitude able to either inhibit one or more of bladdercontractions; rectum contractions; spongiosus and ischiocavernosusmuscle contractions; urination; defecation; ejaculation; and pelvic painof the bladder, urethra, prostate, anus or rectum, thereby obtaining thephysiological response. The physiological response may be one or more ofinhibition of micturition, defecation, ejaculation, bladdercontractions, pelvic pain of bladder, urethra, prostate, anus, orrectum, and inhibition of rectal contractions. In one embodiment, theelectrical pulses range from 1 Hz to 500 Hz, such as 1-50 Hz, 5-20 Hz,or 5 Hz. Voltage may range from 1-50V, such as from 1-20V or from 3-15V,which is suitable for inhibition of bladder contractions; rectumcontractions; bulbospongiosus and ischiocavernosus muscle contractions;for inhibition or treatment of urological conditions, such as overactivebladder (OAB) symptoms including bladder overactivity, urinaryfrequency, urinary urgency, urinary incontinence, interstitial cystitis(IC), urinary retention, and pelvic pain; gastrointestinal conditions,such as fecal incontinence, irritable bowel syndrome (IBS), andconstipation; and sexual conditions, such as premature ejaculation,erectile disorder, and female sexual arousal disorder, which aretreatable by electrical stimulation. The pulses may be appliedintermittently, for example and without limitation, in two or morestimulation intervals of, for example and without limitation, from 0.5to 200 seconds with a rest period of no electrical stimulation able toinhibit bladder or rectal contractions between stimulation intervals.Typically during the rest period, no inhibitory stimulus is applied.During the rest period no electrical signal, or essentially noelectrical signal is applied.

The following are non-limiting examples of the use of electricalstimulation of the foot to inhibit bladder contraction, and areexemplary only and are not intended to limit the scope of the inventionsdescribed herein in any way.

Example 1

Because previous studies have indicated that bladder activity could bemodulated by somatic afferent input, in this study we explored thepossibility that bladder overactivity could be suppressed by activationof afferent nerves in the foot or hand. This was tested in anesthetizedcats by applying electrical stimulation through surface electrodes onthe front or hind foot while monitoring reflex bladder activity.Stimulation of the foot or hand is non-invasive, easily accessible, andconvenient, which could be a widely acceptable treatment for bladderoveractivity if proven to be effective.

Methods: 1. Experimental Setup

Experiments were conducted in a total of 6 female cats (2.6 kg to 3.1kg) under α-chloralose anesthesia (65 mg/kg, I.V. supplemented asnecessary) after induction with isoflurane (2-3% in 02). Systemic bloodpressure was monitored throughout the experiment via a catheter insertedin the right carotid artery. A tracheotomy was performed and a tube wasinserted to keep the airway patent. A catheter for I.V. infusion wasintroduced into the right ulnar vein. The ureters were cut and drainedexternally. A double lumen catheter was inserted through the urethrainto the bladder and secured by a ligature around the urethra. One lumenof the catheter was connected to a pump to infuse the bladder witheither saline or 0.25% acetic acid (AA) at a rate of 0.5-2 ml/min, andthe other lumen was connected to a pressure transducer to measure thepressure change in the bladder. After removal of the fur, surfaceself-adhesive pad electrodes (Grass F-E10ND, Astro-Med Inc., diameter: 1cm) were attached to the skin area on the left hind foot (see FIG. 3).Similarly, electrodes were also attached to the left front foot forstimulation.

2. Stimulation Protocol

Uniphasic rectangular pulses (0.2-1 ms pulse width) were delivered tothe foot via the surface pad electrodes at a frequency of either 5 Hz or20 Hz, based on our previous studies (Tai C, Smerin S E, de Groat W C,Roppolo J R. Pudendal-to-bladder reflex in chronic spinal cord injuredcat. Exp Neurol 2006; 197:225-234 and Tai C, Shen B, Wang J, ChancellorM B, Roppolo J R, de Groat W C: Inhibitory and excitatoryperigenital-to-bladder spinal reflexes in the cat. Am J Physiol RenalPhysiol 2008; 294:F591-F602) that showed pudendal nerve stimulationinhibited bladder activity at 3-7 Hz, but excited bladder at 20 Hz. Thethreshold intensity to induce observable twitching of the toe wasdetermined in each cat by a preliminary test at 5 Hz. Then, stimulationintensities at multiple thresholds of those to induce toe twitching weretested. Stimulation was applied via three combinations of electrodes asshown in FIG. 3 in order to find the effective electrode locations forbladder inhibition. Electrode 1 severed as the cathode in electrodecombinations 1-2 and 1-3, but electrode 2 was the cathode when electrodecombination 2-3 was used.

In the first group of experiments, the bladder was infused with salineto a volume about 100-110% of the bladder volume (i.e. bladder capacity)to induce large amplitude (>30 cmH2O), rhythmic reflex bladdercontractions, and then maintained under isovolumetric conditions. Atthis bladder volume, foot stimulation at 5 and 20 Hz was applied todetermine the effective frequency for bladder inhibition. Thestimulation duration was always longer than the period of at least twobladder contractions to clearly demonstrate an inhibitory effect.

In the second group of experiments, the effect of 5 or 20 Hz stimulationwas tested during a cystometrogram (CMG) which consisted of a slowinfusion of saline (0.5-2 ml/min) starting with an empty bladder todetermine the bladder capacity. Two or three CMGs were preformed withoutstimulation to obtain the control bladder capacity and evaluatereproducibility. Then, foot stimulation was applied during repeatedCMGs. The inhibitory effect was evaluated by measuring the increase inbladder capacity during the stimulation. Stimulation and infusion werestopped after the onset of the first micturition reflex contractionwhich had a large amplitude (>30 cmH2O) and long duration (>30 sec).Control CMGs were also performed between periods of stimulation toexamine if there was any persistent post-stimulation carry-over effect.The bladder was emptied after each CMG and a 5-10 min rest period wasinserted between CMGs to allow the bladder reflex to recover. The twostimulation frequencies were tested in a randomized order in differentanimals.

In the third group of experiments, 0.25% AA was infused into the bladderto induce bladder irritation and overactivity. Then, experiments asdescribed above were repeated in order to determine if the footstimulation could also inhibit the irritation induced bladderoveractivity.

3. Data Analysis

For the analysis of rhythmic bladder activity, the area under bladderpressure curve was measured during the stimulation and was normalized tothe measurement during the same time period before the stimulation. Forrepeated CMG recordings using saline or AA infusion, the bladdercapacities were measured and normalized to the measurement of the firstcontrol CMG during saline infusion. Repeated measurements in the sameanimal during the same experiment were averaged. The normalized datafrom different animals are presented as means±SE. One-sample Student'st-test and paired Student's t-test were used to detect statisticalsignificance (P<0.05).

Results 1. Foot Stimulation During Saline Distension

Under isovolumetric recording conditions with the bladder volume abovethe micturition volume threshold electrical stimulation of the hind footinhibited reflex bladder activity (FIG. 4A-4C), but stimulation of thefront foot failed to induce any inhibitory effect at various stimulationintensities (FIG. 4D, N=2 cats). Therefore, the remaining studiesfocused on hind foot stimulation which is termed foot stimulation in thefollowing text and Figures.

Under isovolumetric conditions foot stimulation at both 5 Hz and 20 Hzinhibited the large amplitude, rhythmic bladder contractions withelectrode combinations 1-2 (FIG. 4A, N=3 cats) and 1-3 (FIG. 4B, N=5cats); whereas with electrode combination 2-3 which was tested in 1 cat,only 5 Hz stimulation was effective (FIG. 4C). Of particular note, 5 Hzstimulation also induced bladder inhibition lasting 5-10 minutes afterthe stimulation was terminated (FIG. 4B). This long-lasting effect wasnot observed with 20 Hz stimulation. These data are of particularimportance indicating that long-lasting inhibitory effect can beobtained from short-term pulse durations. As described in Example 2,additional studies are ongoing that will examine and optimize thelong-term effects from shorter-term stimulation.

Five Hz stimulation at intensities of 3-15 V which ranged from 0.5-2.5times the threshold to induce toe twitching completely inhibited theisovolumetric bladder contractions (N=5 cats), while 20 Hz stimulationat intensities (5-15 V) ranging from 1-2.5 times threshold to induce toetwitching elicited a similar inhibition (90.8±9.1%, P<0.05) of thereflex contractions (N=5 cats). In 2 cats 5 Hz stimulation at anintensity as low as one half of the threshold to induce toe twitchingwas effective in completely inhibiting isovolumetric bladdercontractions with electrodes 1-2 (FIG. 5A), but not with electrodes 1-3(FIG. 5B). Lower stimulation intensities elicited partial inhibitionconsisting of either reduced amplitude bladder contractions (FIG. 5A at0.25 T) or a significantly delayed large amplitude bladder contraction(FIG. 5B at 20 Hz).

Foot stimulation at both 5 Hz and 20 Hz also significantly (P<0.05)increased bladder capacity to 153.2±18.2% and 136.9±14.3%, respectively,of the control bladder capacity (FIGS. 6 and 7). Stimulation intensities(3-12 V) about 1-2.5 times threshold to induce toe movement wereeffective (N=5 cats, 3 cats: electrodes 1-2; 2 cats: electrode 1-3).There was no significant difference between 5 Hz and 20 Hz effects. Theinhibitory effect of foot stimulation was rapidly reversible within 5-10minutes after termination of the stimulation and was repeatable at about20 min intervals. Repeated foot stimulation during multiple CMGrecordings did not elicit a post-stimulation effect on bladder capacity(FIG. 6).

2. Foot Stimulation During Acetic Acid (AA) Irritation

When the bladder was filled with 0.25% AA bladder capacity wassignificantly reduced (FIG. 8A) and large amplitude contractions wereelicited at small bladder volumes (FIG. 7B). Foot stimulation at either5 Hz or 20 Hz completely inhibited the large amplitude, isovolumetricbladder contractions induced by AA irritation (FIG. 8B, N=2 cats).

AA irritation significantly (P<0.05) reduced bladder capacity to20.3±8.9% of the control bladder capacity measured during salineinfusion (FIGS. 9 and 10). Foot stimulation partially reversed theeffect of AA irritation, increasing the bladder capacity to 37.6±2.1%and 43.5±12.0% of the saline control bladder capacity at frequencies of5 Hz and 20 Hz, respectively (FIGS. 9 and 10). There was no significantdifference between 5 Hz and 20 Hz effects.

Discussion

This study showed that electrical stimulation of the foot was effectivein inhibiting reflex bladder activity and increasing bladder capacity inanesthetized cats. Although 5 Hz stimulation was superior to 20 Hz insome cases (FIGS. 4B-C and FIGS. 5-7), there was on average nosignificant difference between these two frequencies in inhibitingreflex bladder activity (FIGS. 7 and 10). These results providedurodynamic evidence indicating that electrical stimulation of the footmight be an effective treatment for bladder overactivity.

All three electrode combinations (FIG. 3) are effective in inhibitingbladder activity (FIG. 4), indicating that afferent activation of aspecific nerve in the foot might not be required. There are two majornerves innervating the foot. Branches from the peroneal nerve run on thedorsal (top of the foot, as is understood in the medical arts) surfaceof the foot, while the tibial nerve mainly branches on the plantar(bottom/sole of the foot, as is understood in the medical arts) surfaceof the foot. Electrical stimulation used in this study probablyactivated nerve branches from both peroneal and tibial nerves,indicating that specifically targeting the posterior tibial nerve ascurrently used in clinical settings might not be necessary. Previousstudies in both cat (Wang J, Liu H, Shen B, Roppolo J R, de Groat WC,Tai C: Bladder inhibition or excitation by electrical perianalstimulation in a cat model of chronic spinal cord injury. BJU Int 2009;103:530-536) and monkey (Sato A, Sato Y, Schmidt R. Reflex bladderactivity induced by electrical stimulation of hind limb somaticafferents in the cat. J Auto Nerv Sys 1980; 1:229-241) have shown thatelectrical stimulation of the peroneal nerve in the hindlimb alsoinhibits reflex bladder activity.

An advantage of foot stimulation is that the nerves in the foot are muchcloser to the skin surface than peroneal or posterior tibial nerve whichis located deeper between the leg muscles. Therefore, electricalactivation of the nerves on the foot requires only surface electrodesand is much easier than the posterior tibial nerve stimulation that isusually performed by inserting a needle electrode close to the nerve.However, it is worth noting that foot stimulation did not induce along-lasting inhibitory effect during repeated CMG tests on the same day(FIG. 5). This is different from the clinical reports of posteriortibial nerve stimulation applied over the course of many weeks where theinhibitory effect could last weeks or months. This difference mightoccur due to different species, presence of anesthesia, or differentstimulation parameters, as well as different stimulation locations. Asindicated in FIG. 4B, certain stimulation parameters producedpost-stimulation effects. Ongoing studies are planned to determineoptimal stimulation conditions for doing so. Nevertheless, thatstimulation is non-invasive means a patient can stimulate their foot atany time for any duration, and even discreetly. As such stimulationresulting in inhibition periods of more than hours or days are not asnecessary as in the case where a patient needs invasive outpatientprocedures to achieve the same results. As shown in FIG. 5A, theinhibitory effect may be achieved at an intensity below the threshold toinduce toe movement.

Electrical stimulation of the front foot in this study failed to inducean inhibitory effect on reflex bladder activity, while stimulation ofthe hind foot was effective. This suggests that the spinal segmentaldistribution of the stimulated somatic afferent pathways is an importantfactor in the efficacy of this type of neuromodulation. In the cat, theafferent projections from the hind foot into the spinal cord exhibitsome segmental overlap in the lumbosacral spinal cord with the afferentprojections from the lower urinary tract (LUT), providing a greaterpossibility of spinal interactions between hind foot and LUT afferentpathways. Therefore, it is probable that the somatic afferent input fromthe hind foot inhibits the micturition reflex at the sacral spinal cordlevel. However, inhibition at a supraspinal site cannot be excluded. Aprevious study in cats (McPherson A. The effects of somatic stimuli onthe bladder in the cat. J Physiol 1966; 185: 185-196) showed that theinhibitory effect on bladder activity elicited by electrical stimulationof the nerves from hindlimb muscles was lost after chronic spinal cordtransaction at the thoracic level, indicating a possible role of thesupraspinal mechanisms in somato-vesical inhibition. The same study alsoshowed that activation of large myelinated afferent nerves (conductionvelocity about 50 m/s) induced the inhibition. Our experiments whichshowed that foot stimulation produced inhibition at stimulationintensities 1-2 times threshold support this conclusion. However anotherstudy (Sato A, Sato Y, Schmidt R. Reflex bladder activity induced byelectrical stimulation of hind limb somatic afferents in the cat. J AutoNerv Sys 1980; 1:229-241) identified a role of small myelinated orunmyelinated hind limb afferent nerves in somato-vesical inhibition inthe cat.

Recent studies in the cats (Tai C, Smerin S E, de Groat W C, Roppolo JR. Pudendal-to-bladder reflex in chronic spinal cord injured cat. ExpNeurol 2006; 197:225-234; Tai C, Shen B, Wang J, Chancellor M B, RoppoloJ R, de Groat W C: Inhibitory and excitatory perigenital-to-bladderspinal reflexes in the cat. Am J Physiol Renal Physiol 2008;294:F591-F602; and Wang J, Liu H, Shen B, Roppolo J R, de Groat W C, TaiC: Bladder inhibition or excitation by electrical perianal stimulationin a cat model of chronic spinal cord injury. BJU Int 2009; 103:530-536)showed that the effect of pudendal nerve stimulation on bladder activitywas dependent on the stimulation frequency. At 3-7 Hz, pudendal nervestimulation significantly inhibited the bladder, but at 20-40 Hz itcould excite the bladder. However, this frequency dependency was notobserved in this study. Foot stimulation significantly inhibited thebladder at both 5 Hz and 20 Hz (FIGS. 4-10), indicating that theunderlying mechanisms of bladder modulation by foot stimulation andpudendal nerve stimulation might be different, even though in our catmodel they appear to be equally effective in suppressing reflex bladderactivity (Tai C, et al. Exp Neurol 2006; 197:225-234 and Tai C, et al.Am J Physiol Renal Physiol 2008; 294:F591-F602). This similar inhibitoryefficacy in cats of foot stimulation and pudendal nerve stimulationwhich has also been shown clinically to be effective in treating bladderoveractivity (Peters K M, Feber K M, Bennett R C: Sacral versus pudendalnerve stimulation for voiding dysfunction: a prospective,single-blinded, randomized, crossover trial. Neurourol Urodyn 2005;24:643-647 and Peters K M, Feber K M, Bennett R C: A prospective,single-blind, randomized crossover trial of sacral vs pudendal nervestimulation for interstitial cystitis. BJU Int 2007; 100:835-839)suggests that foot stimulation might also be a useful treatment forbladder overactivity in humans.

Foot stimulation inhibited not only the bladder activity induced bysaline distention (FIGS. 4-7), but also the bladder overactivity inducedby AA irritation (FIGS. 8-10). However, the marked reduction in bladdercapacity (80%) caused by AA irritation was only partially reversed byfoot stimulation to about 40-50% of the saline control bladder capacity(FIGS. 9 and 10). The ability of foot stimulation to inhibit bladderoveractivity induced by AA irritation is clinically relevant, because AAirritation activates the C-fiber afferents that play an important rolein the generation of bladder overactivity under pathological conditions.Pudendal nerve stimulation produced similar inhibitory effects in the AAmodel in cats (Shen B, et al. Bladder activity modulated bytranscutaneous pudendal nerve stimulation. 2008 Neuroscience MeetingAbstract. Washington D.C.: Society for Neuroscience, 2008).

Further animal studies are needed to explore a broader range of stimuluspatterns and frequencies as well as different electrode placements onthe foot stimulation to determine if efficacy can be improvedparticularly in regard to suppressing bladder overactivity induced byAA. Only continuous stimulation was used in this study, which might notbe the optimal stimulus to induce and maintain the inhibitory effect.Intermittent stimulation with on and off periods might further enhancethe inhibitory effect. Furthermore, different electrode placements whichincrease the probability of activating either cutaneous or muscleafferents should be tested to determine if one type of afferent pathwayis more effective in controlling bladder activity.

This study demonstrated the potential of a non-invasive electricalstimulation method using electrodes applied to skin of the foot toinhibit bladder over activity. Toe movement and sensory responses mightbe a side effect of the treatment, but would be justified by thebenefits of suppressing bladder dysfunction. In summary, the presentstudy indicates that a non-invasive, convenient method to treatoveractive bladder symptoms, and as a result methods of treatment ofurological conditions, such as overactive bladder (OAB) symptomsincluding bladder overactivity, urinary frequency, urinary urgency,urinary incontinence, interstitial cystitis (IC), urinary retention, andpelvic pain; gastrointestinal conditions, such as fecal incontinence,irritable bowel syndrome (IBS), and constipation; and sexual conditions,such as premature ejaculation, erectile disorder, and female sexualarousal disorder, could be developed utilizing transcutaneousstimulation of somatic nerves in the foot.

Example 2

Experiments are conducted in cats to determine the duration ofpost-stimulation inhibition of bladder contractions. Animals areprepared essentially as described in Example 1. Experiments areconducted in female cats (2.6 kg to 3.1 kg) under α-chloraloseanesthesia (65 mg/kg, I.V. supplemented as necessary) after inductionwith isoflurane (2-3% in O2). Systemic blood pressure is monitoredthroughout the experiment via a catheter inserted in the right carotidartery. A tracheotomy is performed and a tube is inserted to keep theairway patent. A catheter for I.V. infusion is introduced into the rightulnar vein. The ureters were cut and drained externally. A double lumencatheter was inserted through the urethra into the bladder and securedby a ligature around the urethra. One lumen of the catheter wasconnected to a pump to infuse the bladder with either saline or 0.25%acetic acid (AA) at a rate of 0.5-2 ml/min, and the other lumen wasconnected to a pressure transducer to measure the pressure change in thebladder. After removal of the fur, surface self-adhesive pad electrodes(Grass F-E10ND, Astro-Med Inc., diameter: 1 cm) are attached to the skinarea on the hind foot essentially as shown in FIG. 3.

Stimulation Protocol

Uniphasic rectangular pulses (0.2-1.0 ms pulse width) at low (5 Hz),medium (20 Hz) or high (30 Hz) frequency are delivered to the electrodepairs. The intensity threshold for inducing toe movement is determinedby gradually increasing the stimulation intensity (voltage). Then,multiples of the threshold intensity are used for foot stimulation.

In the first group of experiments, the bladder is infused with saline toa volume about 100-110% of the threshold volume (i.e. bladder capacity)for inducing large amplitude (>30 cmH2O), rhythmic reflex bladdercontractions, and is then maintained under isovolumetric conditions. Atthis bladder volume, the foot is stimulated at different frequencies (5Hz, 20 Hz or 30 Hz) to determine the effective frequencies forinhibiting bladder activity. The stimulation duration (3-5 minutes) isalways longer than the period of at least two bladder contractions inorder to clearly demonstrate an inhibitory effect. In order to determineif the stimulation increased bladder capacity, several cystometrograms(CMGs) are performed before and after the recording of rhythmicisovolumetric bladder contractions during which short duration nervestimulation is applied multiple times. The CMGs consists of a slowinfusion of saline (0.5-2 ml/min) starting with an empty bladder.

In the second group of experiments, the post-stimulation effect ofprolonged (30 minute) foot stimulation is examined by performingrepeated CMGs. Initially two or three CMGs are preformed withoutstimulation to obtain the control bladder capacity and evaluatereproducibility. Then, two groups of experiments are conducted: 1)Control group without stimulation and 2) Treatment group with footstimulation (further broken down into groups for different electrodecombinations, 1-2, 1-3 and/or 2-3 as described in Example 1. In thetreatment group the bladder volume is maintained at a volume slightlyabove the bladder capacity to induce rhythmic isovolumetric bladdercontractions. Then, foot stimulation (frequency: 5, 20 or 30 Hz;intensity: 2-4 times threshold for inducing toe movement) is applied for30 minutes to inhibit the isovolumetric contractions. After the 30minute stimulation, 5 CMGs are performed within a 1.5-2 hour period toexamine the change of bladder capacity. At the end of the fifth CMG, thebladder volume is again maintained at a volume slightly above thebladder capacity to induce rhythmic isovolumetric contractions, duringwhich a second 30 minute foot stimulation is applied to inhibit thecontractions. The post-stimulation effect on bladder capacity induced bythe second 30 minute stimulation is evaluated by another 5 CMGs repeatedwithin 1.5-2 hours after the termination of the second stimulationtreatment. The stimulation frequency (5, 20 or 30 Hz) was randomizedbetween the first and second 30 minute treatment. In the control groupthe procedures similar to those used in the treatment group areperformed, but the foot stimulation is not applied during either thefirst or the second 30 minute treatment period. Instead, the rhythmicisovolumetric bladder contractions are allowed to continue during each30 minute period. The bladder is emptied after each CMG and a 5-10 minrest period is inserted between CMGs to allow the distended detrusor torecover. The 30 minute stimulation duration is chosen to mimic theclinical application of 30 minute foot stimulation. At the end of thesecond group of experiments after examining the post-stimulation effectof nerve stimulation, the foot stimulation is applied again during theCMGs to determine if the bladder capacity could be further increased.

Animals used in the first group of experiments, in which repeated shortperiods of nerve stimulation are applied during rhythmic isovolumetricbladder contractions, also receive 30 minute stimulation treatmentslater in the experiments in order to compare the effects with thoseelicited in the second group of experiments where short periods ofstimulation are not applied before the 30 minute stimulation.

Data Analysis

For the analysis of rhythmic isovolumetric bladder contractions, thearea under bladder pressure curve is measured during foot nervestimulation and is normalized to the measurement during the same timeperiod before the stimulation. For the repeated CMG recordings, thebladder capacities are measured and normalized to the measurement of thefirst control CMG in each experimental group. Repeated measurements inthe same animal during the same experiment are averaged. The normalizeddata from different animals are presented as means±SE. ANOVA followed byBonferroni post-tests and Student's t-test are used to detectstatistical significance (P<0.05).

Results (Expected)—Foot nerve stimulation inhibits rhythmicisovolumetric reflex bladder contractions; prolonged foot stimulationelicits a persistent post-stimulation increase in bladder capacity; andfoot stimulation during CMGs further increases bladder capacity.

Example 3

Inhibition of bladder contraction in a human patient is tested byplacing electrodes in one or more of three positions on the foot of oneor more human patients. The three positions include: 1) two electrodesattached on the bottom of the foot, between the metatarsals andcalcaneus bones; 2) two electrodes attached on top of the foot: betweenthe talus/navicular and metatarsal bones; and 3) two electrodes attachedone on top and another on the bottom of the foot: across the metatarsalbones.

Patients are divided into at least two groups, one group receivingelectrical stimulus and one group not receiving electrical stimulus.Patients are to drink a liquid, e.g., water, until bladder urgency (anurge to urinate) is felt, at which time biphasic electrical stimulus isapplied with a pulse frequency of between 1-50 Hz, pulse lengths ofbetween 0.1 and 3 ms, and a voltage of between 1 and 50V. Urge tourinate is tested at regular intervals prior to, during and afterelectrical stimulation, and at the same regular intervals fornon-stimulated patients. The urge to urinate is a subjective scaleranging from no urge to urinate and extreme urgency, requiring immediatevoiding (e.g., a scale of 1 to 10 with “1” being no urge to urinate and“10” being extreme urgency. Depending on the electrical stimulusparameters, patients receiving electrical stimulus in the ranges testedare expected to experience reduced urgency during electricalstimulation, and, in many cases after electrical stimulation. Thepatient population for this study also may include or be limited topatients with: urological conditions, such as overactive bladder (OAB)symptoms including bladder overactivity, urinary frequency, urinaryurgency, urinary incontinence, interstitial cystitis (IC), urinaryretention, and pelvic pain; gastrointestinal conditions, such as fecalincontinence, irritable bowel syndrome (IBS), and constipation; andsexual conditions, such as premature ejaculation, erectile disorder, andfemale sexual arousal disorder, with appropriate non-stimulated controlsubjects.

Another experiment could use the patient's urinary diary to record thefrequency, urgency, number of incontinence, etc. before, during andafter foot stimulation treatment.

Yet another experiment could use urodynamic test (e.g., cyctometrogram)to record bladder activity (e.g., detrusor overactivity, bladdercapacity, first desire to void, micturition pressure and duration, etc.)before, during, and after foot stimulation treatment.

Having described this invention, it will be understood to those ofordinary skill in the art that the same can be performed within a wideand equivalent range of conditions, formulations and other parameterswithout affecting the scope of the invention or any embodiment thereof.All references cited herein are incorporated herein by reference intheir entirety for their technical disclosure.

What is claimed is:
 1. A method of treating fecal incontinence in apatient, comprising: transcutaneously delivering pulsed electricalenergy directly to a foot of the patient through a device comprising aplurality of electrodes placed on the skin of the patient's foot, thepulsed electrical energy comprising electrical pulses having a frequencyranging from 1 Hz to 500 Hz and a voltage ranging from 1 V to 50 V, theelectrical pulses configured to inhibit rectal contractions in thepatient, wherein the electrodes are arranged such that: two or moreelectrodes are in contact with the skin on a dorsal surface of thepatient's foot, and at least two of the electrodes have oppositepolarities; two or more electrodes are in contact with the skin on aplantar surface of the patient's foot, and at least two of theelectrodes have opposite polarities; or at least one electrode is incontact with the skin on the dorsal surface of the patient's foot and atleast one electrode is in contact with the skin on the plantar surfaceof the patient's foot, and at least one electrode in contact with theskin on the dorsal surface of the patient's foot has an oppositepolarity from at least one electrode in contact with the skin on theplantar surface of the patient's foot.
 2. The method of claim 1, whereinthe electrical pulses are applied by one or more surface electrodes onskin of the dorsal side of the foot about one or more metatarsal bonesand one or more surface electrodes of opposite polarity on skin of theplantar side of the foot about one or more metatarsal bones.
 3. Themethod of claim 1, wherein the electrical pulses are applied by one ormore surface electrodes on skin of the dorsal side of the foot about oneor more metatarsal bones and one or more surface electrodes of oppositepolarity on skin of the dorsal side of the foot about one or more of thetalus, cuboid, intermediate cuneiform, lateral cuneiform or navicularbones.
 4. The method of claim 1, wherein the electrical pulses areapplied by one or more surface electrodes on skin of the plantar side ofthe foot about one or more metatarsal bones and one or more surfaceelectrodes of opposite polarity on skin of the plantar side of the footabout the calcaneous bone.
 5. The method of claim 1, in which the pulsesare biphasic.
 6. The method of claim 5, in which the pulses aresymmetrical, square, or rectangular.
 7. The method of claim 5, in whichthe pulses are charge balanced.
 8. The method of claim 1, wherein thepulses are applied in two or more stimulation intervals of from 0.5 to200 seconds with a rest period of no electrical stimulation able toinhibit rectal contractions between stimulation intervals.
 9. The methodof claim 1, in which the pulses are applied at a voltage less than anintensity threshold to induce toe movement (T) in a patient.
 10. Themethod of claim 1, in which the electrical pulses are applied byelectrodes in a garment electrode.
 11. The method of claim 1, in whichthe pulse frequency ranges from 1 Hz to 50 Hz.
 12. The method of claim1, in which the pulse frequency ranges from 5 Hz to 20 Hz.
 13. Themethod of claim 1, in which the pulse frequency is approximately 5 Hz.14. The method of claim 1, in which the voltage ranges from 3V to 12V.15. The method of claim 1, in which the voltage ranges from 0.5 T to 4T, where T is a toe-twitch threshold of the patient.
 16. The method ofclaim 1, in which the duration of pulses ranges from 0.1 ms to 3 ms orfrom 0.2 ms to 1 ms.
 17. The method of claim 1, in which the duration ofpulses is approximately 1 ms.
 18. The method of claim 1, wherein theelectrical pulses have a frequency of about 20 Hz.
 19. The method ofclaim 1, wherein the fecal incontinence is associated with irritablebowel syndrome or an inflammatory bowel disease in a patient.
 20. Amethod of treating fecal incontinence in a patient, comprising:transcutaneously delivering pulsed electrical energy directly to a footof the patient through a device, the device comprising: an electrodeassembly comprising a plurality of inward facing electrodes, theassembly configured such that one or more of the electrodes contacts theskin of the patient on a plantar surface of the patient's foot and/orone or more of the electrodes contacts the skin of the patient on thedorsal surface of the patient's foot, wherein at least one of theelectrodes has a first polarity and another of the electrodes has anopposite polarity, wherein the pulsed electrical energy compriseselectrical pulses having a frequency ranging from 1 Hz to 500 Hz and avoltage ranging from 1 V to 50 V, the electrical pulses are configuredto inhibit rectal contractions in the patient.